1. Field of the Invention
The present invention relates to a novel granulation process for the preparation of direct tabletting formulations for pharmaceutically-active ingredients, or direct pharmaceutical tabletting aids using pharmaceutical excipients. In particular, this novel granulation process is performed under the condition of low moisture content or low content of a pharmaceutically-acceptable solvent by subjecting a mixture containing one or more diluents and/or active ingredients; a binder; and optionally a disintegrant, to heating in a dosed system under mixing by tumble rotation.
The invention furthermore relates to tablets, capsules, or pellets, which comprise such direct tabletting formulations or tabletting aids, and to processes for producing the tablets, capsules, or pellets comprising the direct tabletting formulations or tabletting aids according to the present invention.
2. Description of the Related Art
The modern tabletting process often involves the compression of direct tabletting aids (excipients), along with active substances, into a tablet under pressure. Direct tabletting aids are required to have not only good flow properties and binding capacity but also a high uptake capacity for active substances, which are generally difficult to compress. This is also true for developing a directly compressible formulation for any pharmaceutically active ingredients. Optimally, the resulting tablets are generally intended to have low friability and high fracture resistance. Some of these requirements are contradictory. For example, high tablet fracture resistance is associated with the presence of many points of contact between the diluent (filler) or pharmaceutically active ingredient and binder inside the tablet, which is usually achieved with the use of diluent and binder in the form of fine particles. However, fine-particle substances in turn have poor flow properties, limiting their suitability for use in high-speed processes. Attempts have been made over the years to improve or modify the diluents (or pharmaceutically active ingredient) and binders so that these contradictory properties are substantially eliminated while retaining the beneficial characteristics.
Direct tabletting aids of this type, which are also referred to as xe2x80x9cmultipurpose excipientsxe2x80x9d, are, as a rule, preparations which are produced via specific processes, consist of a plurality of components and are also mentioned as co-processed materials in the literature. For example, a combination of xcex1-lactose monohydrate and powdered cellulose is disclosed for direct tabletting in DE-C 3 506 276. Although this composition has a high binding capacity, it has no disintegration-promoting properties, especially when the compressive forces are relatively high. Another combination of xcex1-lactose monohydrate and polyvinyl pyrrolidone as binder, and crosslinked, insoluble polyvinyl pyrrolidone to promote disintegration, disclosed in DE-A 35 05 433 (U.S. Pat. No. 5,006,345), has excellent flow properties and results, without further addition of a disintegrant, in rapidly disintegrating tablets. However, this direct tabletting aid is less suitable for high-dose active substances whose compressibility is poor, because its uptake capacity for active substances to form tablets with sufficient mechanical stability is limited.
U.S. Pat. No. 5,840,769 described a direct tabletting aid using microcrystalline cellulose (MCC) as diluent, soluble polyvinyl pyrrolidone (PVP) as binder, and crospovidone as disintegrant. It was taught that this product can be prepared by conventional wet granulation methods such as mixer granulation, Shugi granulation, extrusion, perforated plate granulation, or preferably, fluidized bed granulation. Wet Granulation of excipients (diluents or disintegrants) or pharmaceutically active ingredients, using a binder, such as PVP, dissolved in water and/or organic solvents, is a common practice. However despite its widespread usage, wet granulation is a process with certain fundamental drawbacks.
The technique of wet granulation is often employed in the pharmaceutical industry to improve the properties of a tabletting mixture. Wet granulation involves the addition of a binder solution to aggregate smaller particles into larger granules for the improvement of powder flowability. Due to the even distribution of the binder on the surface of the diluent or active ingredient, thereby increasing the points of contact, binding efficiency of the resulting granules is often increased and results in greater tablet strength. Granulation also serves to reduce dust in the tabletting mixture and improve workplace conditions during the automated tabletting processes. Another benefit of wet granulation is that it helps to facilitate the uniform blending of components in a tabletting mixture.
Wet granulation requires a large amount of liquid to be added, which necessitates tanks and handling equipments. Since the liquid used in wet granulation must subsequently be removed, a drying step is also needed, thereby requiring drying equipment and further complicating the manufacturing process, as well as significantly increasing the energy, cost and production time of the overall process. Furthermore, the use of large amounts of volatile organic solvent as granulating fluid may be harmful to the operator as well as the environment Special precaution and equipments are necessary to avoid explosions and protect workers from exposure to these solvents.
Another disadvantage of wet granulation is that, in certain instances, the presence of excessive moisture can negatively affect the ingredients in the tabletting formulation. For example, as discussed in U.S. Pat. No. 6,103,219, it is known that the exposure of microcrystalline cellulose to moisture in the wet granulation process severely reduces the compressibility of this excipient, mainly due to softening of the cellulose fibers. This loss of tabletting strength dictates that a larger amount of the MCC may be needed to obtain an acceptably compressed final product, especially when a high dose of active ingredients is sought The additional amount of MCC required not only adds cost to the preparation, but more importantly, increases the size and bulk of the resulting tablet, making it more difficult to swallow. The loss of compressibility of microcrystalline cellulose caused by wet granulation has long been considered a problem in the art for which there has been no satisfactory solution.
The literature is flooded with various examples for the use of PVP (or other binders) in wet granulation (eg., WO 93/09763; WO 00/06125; U.S. Pat. No. 4,968,509; U.S. Pat. No. 5,200,193; U.S. Pat. No. 5,462,747). By in large, wet granulation with a large amount of aqueous or alcoholic solution to dissolve the binder is still the most popular way to prepare granules for tabletting or to manufacture matrix-forming material for sustained-release dosage forms Considering the drawbacks of wet granulation, it would be desirable to obtain an alternative granulation process which improves the flowability, while retaining or improving other tabletting features, such as tablet hardness, of a direct tabletting formulation or aid, without the extensive use of granulation liquid as employed in wet granulation.
Thus, the object of the present invention is to develop an alternative granulation process which utilizes considerably less water or solvent than the traditional wet granulation method.
Another object of the present invention is to utilize the granulation process for providing direct tabletting formulations with good flow properties and binding capacity to form tablets of low friability and adequate hardness.
A further object of the present invention is to utilize the granulation process for producing direct tabletting aids which, while having good flow properties and binding capacity to form tablets of low friability and adequate hardness, have a high uptake capacity for active substances whose tablettability is poor.
An additional object of the present invention is to utilize the granulation process for providing direct tabletting formulations or aids which, while having good flow properties and binding capacity to form tablets of low friability and adequate hardness, have an adequate disintegration activity for active substances.
Further objects and advantages of this invention will become apparent from a consideration of the ensuing discussions and examples.
As a result of various investigations carried out to find a novel method achieving the purpose, the present inventors found that when a finely-divided powder of binder is mixed with diluent excipients such as cellulose powder, microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, or active substances, such as acetaminophen or ascorbic acid, and subjected to heating in a closed system with a low moisture content or low content of a pharmaceutically-acceptable solvent, while mixed by rumble rotation, it was possible to obtain direct tabletting formulations or aids with favorable properties not observed in the starting materials.
Thus, the present invention provides a novel method to prepare a direct tabletting formulations or aids using a finely-divided powder of binder to granulate excipients or active substances in a closed system with a low moisture content or low content of a pharmaceutically-acceptable solvent while being subjected to heating and mixing by tumble rotation.
The present invention, termed xe2x80x9cthermal adhesion granulationxe2x80x9d (TAG), is a novel granulation method and will be described in detail below.
The present invention provides a granulation process for preparing direct tabletting formulations containing pharmaceutically-active ingredients, or direct tabletting aids (i.e., aids which contain no active substances), by subjecting the mixture of A) and B) in the following to heating at a temperature range of from about 30 to about 130xc2x0 C., preferably from about 40 to about 110xc2x0 C., and in particular from about 60 to about 105xc2x0 C., under the condition of from about 0.1 to about 20% initial moisture content and/or from about 0.1 to about 20% initial content of a pharmaceutically-acceptable organic solvent, in a dosed system under mixing by tumble rotation until the formation of granules:
A) from about 5 to about 99% by weight, preferably from about 10 to about 90% by weight, of one or more diluent (filler) excipients suitable for tabletting, and/or from 0 to about 99% by weight, preferably from about 10 to about 90% by weight, of a pharmaceutically-active ingredient;
B) from about 1 to about 95% by weight, preferably from about 5 to about 50% by weight, of a binder excipient; and optionally,
C) from 0 to about 10% by weight of disintegrant excipient, which can be added to the above mixture of A) and B) before or after granulation.
The granulation of a mixture of components A), B) and optionally C), according to the present invention, must be conducted in a closed system with initial moisture content of the mixtures in the range of from about 0.1 to about 20%, preferably in a range of from about 2 to about 15%, and more preferably from about 4 to about 10%, as determined by a moisture balance (eg, Ohaus, Japan). Alternatively, granulation may be accomplished with a pharmaceutically-acceptable organic solvent (e.g., ethanol) at an initial solvent content of the mixtures in the range of from about 0.1 to about 20%, preferably in a range of from about 0.1 to about 10%, and more preferably from about 0.5 to about 5%.
xe2x80x9cTumble rotationxe2x80x9d is defined as rotation of a container about an inner horizontal axis, whereby the powder mixture mass inside the container is made to slide, roll, flow, fall or otherwise move along the inner wall of the container.
The diluent excipient(s) in component A) may be selected from powdered cellulose, microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, tribasic calcium phosphate, mannitol, sorbitol, sucrose, dextrose, cellulose acetate, hydroxypropyl methylcellulose, and others, or a combination thereof, preferably powdered cellulose, microcrystalline cellulose, lactose, starch, and dibasic calcium phosphate. In a preferred embodiment of the present invention, the microcrystalline used is grade 101, wherein about 90% of the particles are in the range from about 1 xcexcm to about 125 xcexcm, and the average particle size is from about 10 xcexcm to about 70 xcexcm.
The pharmaceutically-active ingredient in component A) may be selected from acetaminophen, ascorbic acid, nifedipine, ibuprofen, aspirin, and others, or a combination thereof, preferably acetaminophen and ascorbic acid.
Although stable tablets can usually be obtained with diluent excipient such as powdered cellulose, microcrystalline cellulose, lactose, starch, and dibasic calcium phosphate, even with low compressive forces, the flow properties of these fine powders are generally poor due to the relatively small particle sizes. Granulation with binders improves the flow properties due to the increase in particle size talking place during granulation.
For component B), the binder excipient may be selected from soluble polyvinyl pyrrolidone (PVP), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), low-substituted hydroxypropylcellulose (L-HPC), sodium carboxymethylcellulose, methyl cellulose, ethyl cellulose, sugar, and others, or a combination thereof, preferably polyvinyl pyrrolidone and hydroxypropylcellulose. Further, the binder excipient may contain from 0 to about 10% (by weight with respect to the binder) of one or more anticaking agents, such as dibasic calcium phosphate anhydrous, silicon dioxide, or calcium silicate, preferably dibasic calcium phosphate anhydrous.
For component C), disintegrating agents such as crospovidone (PVP-CL), sodium starch glycolate (SSG), reticulated (crosslinked) carboxymethylcellulose (CMC-CL), low-substituted hydroxypropylcellulose (L-HPC), and others, or a combination thereon may be mixed with the mixture during granulation (intragranular) or after granulation (extragranular) to further facilitate the disintegration of the resulting tablets or capsules.
Soluble polyvinyl pyrrolidone (PVP), used in the present invention as a preferred binder in one embodiment of the thermal adhesion granulation process, is a finely-divided powder applied extensively in the pharmaceutical industry as a tabletting binder, either for wet granulation or direct compression. Generally, the polyvinyl pyrrolidones have a K value of from about 12 to about 120. Particularly preferred polyvinyl pyrrolidones according to the invention have a K value of from about 20 to about 95, in particular from about 25 to about 35. For the definition of the K value, reference may be made to the povidone monograph in U.S. Pat. No. 24/NF19 (2000).
Thermal adhesion granulation is essentially a dry process in which the binder is dry-blended into the mixture, rather than added as a solution. To optimize the binding efficiency, it is desirable to use a finely-divided binder powder to maximize the contact points between the binder and the diluent or active ingredients. Certain binders, such as PVP, are highly hygroscopic and become sticky and tacky with the absorption of moisture. Caking of fine-particle PVP during storage, as a result of absorbing moisture from the atmosphere, is a common occurrence. To help promote and maintain the uniform distribution of the binder as a fine powder (component B) when mixed with the diluents and/or active ingredients (component A), the binder used in this invention can be first mixed with from 0 to about 10%, preferably from about 0.01 to about 10%, more preferably from about 2 to about 4% (by weight with respect to binder), of an anticaking agent. In applying the anticaking agent, the binder and the anticaking agent should be blended together, pulverized to a fine powder in a blender, then passed through a 200-mesh sieve. This binder/anticaking agent mixture can then be used for granulation with component A and optionally component C.
The low water or solvent requirement for TAG stems from the fact that the granulation is conducted in a closed system. Because vapors generated from heating (from the added wetting solution plus any inherent moisture of the powder mass) are prevented from escaping from the system, granulation fluid usage is maximized and the granulation can be accomplished with a minimal addition of moisture or solvent. It is believed that the heating of the powder mass may also result in the transfer of certain inherent moisture in the diluents to the binder. A preferred embodiment of TAG is that the heat distribution on the surface of the granulation vessel should be, in some manner, slightly non-uniform, such that when the powder mass is heated, the evolved water or solvent vapor can condense on a portion of the inner surface of the vessel which is comparatively cooler. Since binders, e.g., PVP, are generally highly hygroscopic, any moisture present in the system, especially in the form of condensation, is scavenged by the binder, which then becomes sticky and tacky with the absorption of moisture and heat. Because the binder was uniformly predispersed among the diluents/active ingredients as a fine powder prior to granulation, the increasing adhesiveness of the binder results in the cohesion of neighboring particles and ultimately the formation of granules as the powder mass is mixed within the dosed vessel. The optimal temperature range for TAG is system-specific, and depends on factors such as the type and amount of diluents, binder and granulation fluid used. For example, when an organic solvent rather than water is used as the granulation fluid, a lower temperature may be necessary.
Compared with the known techniques of mixing and tabletting active substances with powdered cellulose, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone and water-soluble polyvinyl pyrrolidone, as described in, for example, EP-A 273 209 or U.S. Pat. No. 5,840,769, a tabletting process using the direct tabletting aid according to the invention is distinguished by being a significantly simplified production process with relatively low energy requirement, minimal pollution potential and a wide range of applicability with regard to the excipients, binders and active substance employed. These advantages can be attributed mainly to the low amount or water or organic solvent required by the present invention as granulation fluids to produce granules which are comparable or superior in performance compared to granules derived from existing technologies.
The present invention, xe2x80x9cthermal adhesion granulation,xe2x80x9d differs from the traditional wet granulation approach in several important aspects:
1) In thermal adhesion granulation, a low amount of moisture is added to the tabletting mixture already containing diluent excipients and binder, whereas in wet granulation the binder is generally dissolved in the granulation fluid then mixed with the diluent excipients.
2) Thermal adhesion granulation resembles a xe2x80x9cdryxe2x80x9d process in that the granulation fluid requirement (water or organic solvent) of thermal adhesion granulation is significantly less than that in wet granulation.
3) With the exception of the drying step, wet granulation is typically conducted at the ambient temperature, whereas in thermal adhesion granulation the tabletting mixture is heated to promote the formation of granules.
4) In wet granulation, the mixing requirement is typically accomplished by either directly stirring the powder/fluid mixture or mass with a blade, arm, propeller, chopper, or other types of mechanical stirring means (e.g., shear granulation using a planetary mixer, high speed mixer/granulator), or suspending the powder in a hot stream of air while spraying with a binder solution (fluidized bed granulators). In the former, granules are formed by sieving the wet mass, while in the latter, granules are formed by coating the particles with the binder solution. In thermal adhesion granulation, granules are formed during mixing of the moist powder under continuous tumble rotation, as the heated powder mass flows within the container and agglomerates with the aid of the binder.
5) Wet granulation involves significant post-granulation steps of drying and milling to form the desired granules. These steps are unnecessary in the present invention due to the low amount of moisture introduced to the tabletting mixture.
6) Conventional granulation methods are typically conducted in open systems. The present invention of thermal adhesion granulation is conducted in a closed system.
An advantage of being able to conduct granulation in a dosed system is that system conditions may be manipulated to a high degree of specificity, depending on the reactor configuration. For example, in a mixer capable of heating and vacuum drying, the headspace gas may either be withdrawn to a complete or partial vacuum, or purged and replaced with inert or nonreactive gases (e.g., nitrogen or helium). Although heat is applied, granulation in a system devoid of oxygen can lead to greater drug stability as well as decreased likelihood of solvent explosion. In the same reactor, a post-granulation vacuum drying step could also be applied for efficient solvent recovery.
Another major advantage of granulating pharmaceutical products in a closed system is that it helps to minimize the generation of dust during powder processing. This technique serves to contain fine-powder active ingredients whose spread or loss from the system is not desirable due to their cost or biological activity. Just as applicable, the TAG process may be utilized in other industries such as nutraceutical, food, or animal feed, among others.
The application of TAG may be further extended to the granulation of other industrial or agricultural productsxe2x80x94such as fertilizer or pesticide powders, granules or pelletsxe2x80x94for which granulation it a closed system may help to reduce the generation of toxic or hazardous dust.
Thee present invention is also related to a powder mixture of soluble polyvinyl pyrrolidone containing from about 0.01 to about 10% (by weight with respect to the polyvinyl pyrrolidone) of dibasic calcium phosphate anhydrous.
The present invention is further related to a direct tabletting formulation or aid comprising:
i) from about 5 to about 99% by weight of powder cellulose, microcrystalline cellulose, lactose, starch, or dibasic calcium phosphate;
ii) from 0 to about 99% by weight of acetaminophen or ascorbic acid;
iii) from about 1 to about 95% by weight of a soluble polyvinyl pyrrolidone which contains from about 0.01 to about 10% (by weight with respect to the polyvinyl pyrrolidone) of dibasic calcium phosphate anhydrous; and
iv) from 0 to about 10% by weight of crospovidone, sodium starch glycolate, reticulated carboxymethylcellulose, or low-substituted hydroxypropylcellulose.
The present invention furthermore relates to tablets, capsules, or pellets, which comprise the direct tabletting formulations or tabletting aids disclosed in the present invention, and to processes for producing such said tablets, capsules, or pellets.